Studies on the pathogenesis of drug-resistant herpes simplex virus infections in humans and development of a novel and rapid sensitivity assay system

人类耐药单纯疱疹病毒感染发病机制的研究及新型快速敏感性测定系统的开发

• 批准号: 21591402
• 负责人: SAIJO Masayuki
• 金额: $ 2.91万
• 依托单位: National Institute of Infectious Diseases
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21591402/
• 关键词: ウイルス感染症; 薬剤耐性; 免疫不全; 単純ヘルペス; 単純ヘルペスウイルス; アシクロビル; ガンシクロビル; 薬剤感受性; 迅速診断; 臓器移植; 単純ヘルペイウイルス

A life-long HSV-1 infections in a child with a congenital immunodeficiency syndrome, Wiskott-Aldrich syndrome(WAS), was closely observed virologically and clinically. The observation based on the virological analyses demonstrated that acyclovir(ACV), anti-HSV-1 drug-resistant HSV-1 infections emerged during the course of his life. Furthermore, it was revealed that virus thymidine kinase(vTK)-deficient and highly ACV-resistant HSV-1 could reactivate in humans, despite vTK-deficient HSV-1 was reported to be able to establish latency in neuronal ganglia, but not reactivate from latency. The vTK-deficient HSV-1 in the patient was revealed to reactivate from latency by the assistance of the vTK-positive and ACV-sensitive HSV-1 when it reactivated. An efficacious rapid antiviral sensitivity assay system was developed. The sensitivity of HSV-1 could be determined by measuring the inhibitory effect of ACV and other vTK-associated drugs on the replication of vTK-deficient HSV-1 in 293T cells expressed with recombinant vTK of the interest virus by transfection of the cells with mammalian cell expression vectors. The interest virus would be determined to be ACV-resistant if the inhibitory effect was significantly less than that in the cells expressed with wild? type vTK. The system can be applied not only to HSV-1, but also to varicella zoster virus.

对1例先天性免疫缺陷综合征（Wiskott-Aldrich综合征（WAS））患儿的HSV-1终身感染进行了病毒学和临床观察。根据病毒学分析的观察表明，阿昔洛韦（ACV），抗HSV-1耐药HSV-1感染出现在他的生活过程中。此外，还揭示了病毒胸苷激酶（vTK）缺陷型和高度ACV抗性HSV-1可在人体中再活化，尽管据报道vTK缺陷型HSV-1能够在神经元神经节中建立潜伏期，但不能从潜伏期再活化。患者体内vTK缺陷型HSV-1在vTK阳性和ACV敏感型HSV-1的辅助下从潜伏期重新激活。建立了一种高效的抗病毒药物敏感性快速检测系统。HSV-1的敏感性可通过测定ACV和其他vTK相关药物对vTK缺陷型HSV-1在293 T细胞中复制的抑制作用来确定，所述293 T细胞通过用哺乳动物细胞表达载体转染细胞表达目的病毒的重组vTK。如果目的病毒的抑制效果显著低于野生型表达的细胞，则确定目的病毒是ACV抗性的。vTK型。该系统不仅适用于HSV-1，也适用于水痘带状疱疹病毒。

项目成果

293T細胞を用いた単純ヘルペスウイルスならびに水痘帯状疱疹ウイルス組換えチミジンリン酸化酵素の発現と薬剤感受性試験への応用

293T细胞表达单纯疱疹病毒和水痘带状疱疹病毒重组胸苷激酶及其在药敏试验中的应用

• 发表时间: 2009
• 作者: 塩田智之;飯塚愛恵;森川茂;倉根一郎;水口雅;西條政幸
• 通讯作者: 西條政幸

造血幹細胞移植患者における単純ヘルペスウイルス1型（HSV-1）の口腔内への排出状況と薬剤耐性HSV-1の出現

造血干细胞移植患者1型单纯疱疹病毒（HSV-1）口腔排泄状况及耐药HSV-1的出现

• 发表时间: 2011
• 作者: Omatsu T;Moi ML;Hirayama T;Takasaki T;Nakamura S;Tajima S;Ito M;Yoshida T;Saito A;Katakai Y;Akari H;Kurane I.;入江 崇;王麗欣，辻正徳，谷口修一，西村秀一，伊藤（高山）睦代，山口（木下）一美，西條政幸
• 通讯作者: 王麗欣，辻正徳，谷口修一，西村秀一，伊藤（高山）睦代，山口（木下）一美，西條政幸

Long-term observation of HSV-1 infections in a child with Wiskott-Aldrich syndrome and possible reactivation mechanism of TK-negative HSV-1 in humans

Wiskott-Aldrich 综合征儿童 HSV-1 感染的长期观察及人类 TK 阴性 HSV-1 可能的再激活机制

• 期刊: Japanese Journal of Infectious Diseases
• 影响因子: 2.2
• 作者: Shiota T;Kurane I;Morikawa S;Saijo M
• 通讯作者: Saijo M

DNAポリメラーゼ変異によるアシクロビルやフォスカルネット耐性単純ヘルペスウイルス1型の他の抗ウイルス薬に対する薬剤感受性

DNA聚合酶突变导致阿昔洛韦和膦甲酸耐药1型单纯疱疹病毒对其他抗病毒药物的药物敏感性

• 发表时间: 2010
• 作者: Shigeta T;Imadome K;Fukuda A;Umezawa A;西條政幸;王麗欣,木下一美,中道一生,伊藤睦代,錫谷達夫,倉根一郎,西條政幸
• 通讯作者: 王麗欣,木下一美,中道一生,伊藤睦代,錫谷達夫,倉根一郎,西條政幸

Expression of herpes simplex virus type 1 recombinant thymidine kinase and its application to a rapid antiviral sensitivity assay

单纯疱疹病毒1型重组胸苷激酶的表达及其在快速抗病毒敏感性测定中的应用

• 发表时间: 2011
• 期刊: Antiviral Research
• 影响因子: 7.6
• 作者: Shiota T;Wang L;Ito M;Iizuka I;Ogata M;Tsuji M;Nishimura H;Taniguchi S;Morikawa S;Kurane I;Mizuguchi M;Saijo M.
• 通讯作者: Saijo M.